Citations

ObjectiveThe new criteria for preclinical Alzheimer disease (AD) proposed 3 stages: abnormal levels of β‐amyloid (stage 1), stage 1 plus evidence of brain injury (stage 2), and stage 2 plus subtle cognitive changes (stage 3). However, a large group of subjects with normal β‐amyloid biomarkers have evidence of brain injury; we labeled them as the “suspected non‐Alzheimer pathophysiology” (sNAP) group. The characteristics of the sNAP group are poorly understood.MethodsUsing the preclinical AD classification, 430 cognitively normal subjects from the Mayo Clinic Study of Aging who underwent brain magnetic resonance (MR), 18fluorodeoxyglucose (FDG), and Pittsburgh compound B positron emission tomography (PET) were evaluated for FDG PET regional volumetrics, MR regional brain volumetrics, white matter hyperintensity volume, and number of infarcts. We examined cross‐sectional associations across AD preclinical stages, those with all biomarkers normal, and the sNAP group.ResultsThe sNAP group had a lower proportion (14%) with apolipoprotein E ε4 genotype than the preclinical AD stages 2 + 3. The sNAP group did not show any group differences compared to stages 2 + 3 of the preclinical AD group on measures of FDG PET regional hypometabolism, MR regional brain volume loss, cerebrovascular imaging lesions, vascular risk factors, imaging changes associated with α‐synucleinopathy, or physical findings of parkinsonism.InterpretationCognitively normal persons with brain injury biomarker abnormalities, with or without abnormal levels of β‐amyloid, were indistinguishable on a variety of imaging markers, clinical features, and risk factors. The initial appearance of brain injury biomarkers that occurs in cognitively normal persons with preclinical AD may not depend on β‐amyloidosis. ANN NEUROL 2013;73:472–480

Object The goal of vestibular schwannoma surgery is tumor removal and preservation of neural function. Intraoperative facial nerve (FN) monitoring has emerged as the standard of care, but its role in predicting long-term facial function remains a matter of debate. The present report seeks to describe and critically assess the value of applying current at supramaximal levels in an effort to identify patients destined for permanent facial paralysis. Methods Over more than a decade, the protocol for stimulating and assessing the FN during vestibular schwannoma surgery at the authors' institution has consisted of applying pulsed constant-current stimulation at supramaximal levels proximally and distally following tumor resection to generate an amplitude ratio, which subtracted from 100% yields the degree to which the functional integrity of the FN “dropped off” intraoperatively. These data were prospectively collected and additional variables that might impact postoperative FN function were retrospectively reviewed from the medical record. Only patients with anatomically intact FNs and > 12 months of follow-up data were analyzed. Results There were 267 patients available for review. The average posterior fossa tumor diameter was 24 mm and the rate of long-term good (House-Brackmann Grade I–II) FN function was 84%. Univariate logistic regression analysis revealed that prior treatment, neurofibromatosis Type 2 status, tumor size, cerebellopontine angle extension, subjectively thinned FN at the time of operation, minimal stimulation threshold, percent dropoff by supramaximal stimulation (SMS), and postoperative FN function all correlated statistically (p < 0.05) with long-term FN function. When evaluating patients with significant FN weakness at the time of hospital discharge, only the percent dropoff by SMS remained a significant predictor of long-term FN function. However, the positive predictive value of SMS for long-term weakness is low, at 46%. Conclusions In a large cohort of patients, the authors found that interrogating intraoperative FN function with SMS is safe and technically simple. It is useful for predicting which patients will ultimately have good facial function, but is very limited in identifying patients destined for long-term facial weakness. This test may prove helpful in the future in tailoring less than gross-total tumor removal to limit postoperative facial weakness.

Background Two recent studies identified a mutation (p.Asp620Asn) in the vacuolar protein sorting 35 gene as a cause for an autosomal dominant form of Parkinson disease . Although additional missense variants were described, their pathogenic role yet remains inconclusive. Methods and results We performed the largest multi-center study to ascertain the frequency and pathogenicity of the reported vacuolar protein sorting 35 gene variants in more than 15,000 individuals worldwide. p.Asp620Asn was detected in 5 familial and 2 sporadic PD cases and not in healthy controls, p.Leu774Met in 6 cases and 1 control, p.Gly51Ser in 3 cases and 2 controls. Overall analyses did not reveal any significant increased risk for p.Leu774Met and p.Gly51Ser in our cohort. Conclusions Our study apart from identifying the p.Asp620Asn variant in familial cases also identified it in idiopathic Parkinson disease cases, and thus provides genetic evidence for a role of p.Asp620Asn in Parkinson disease in different populations worldwide.

AbstractThe Alzheimer's Disease Neuroimaging Initiative (ADNI) three‐dimensional T1‐weighted magnetic resonance imaging (MRI) acquisitions provide a rich data set for developing and testing analysis techniques for extracting structural endpoints. To promote greater rigor in analysis and meaningful comparison of different algorithms, the ADNI MRI Core has created standardized analysis sets of data comprising scans that met minimum quality control requirements. We encourage researchers to test and report their techniques against these data. Standard analysis sets of volumetric scans from ADNI‐1 have been created, comprising screening visits, 1‐year completers (subjects who all have screening, 6‐ and 12‐month scans), 2‐year annual completers (screening, 1‐year and 2‐year scans), 2‐year completers (screening, 6‐months, 1‐year, 18‐months [mild cognitive impaired (MCI) only], and 2‐year scans), and complete visits (screening, 6‐month, 1‐year, 18‐month [MCI only], 2‐year, and 3‐year [normal and MCI only] scans). As the ADNI‐GO/ADNI‐2 data become available, updated standard analysis sets will be posted regularly.

Object The goals of this retrospective cohort study were as follows: 1) to describe the long-term prevalence and timing of hearing deterioration following low-dose (12- to 13-Gy marginal dose) stereotactic radiosurgery (SRS) for vestibular schwannoma (VS); and 2) to identify clinical variables associated with long-term preservation of useful hearing following treatment. Methods Patients with serviceable hearing who underwent SRS for VS between 1997 and 2002 were studied. Data including radiosurgery treatment plans, tumor characteristics, pre- and posttreatment pure tone average, speech discrimination scores, and American Academy of Otolaryngology–Head and Neck Surgery hearing class were collected. Time to nonserviceable hearing was estimated using the Kaplan-Meier method. Univariate and multivariate associations with time to nonserviceable hearing were evaluated using Cox proportional hazards regression models. Results Forty-four patients met the study criteria and were included. The median duration of audiometric follow-up was 9.3 years. Thirty-six patients developed nonserviceable hearing at a mean of 4.2 years following SRS. The Kaplan-Meier estimated rates of serviceable hearing at 1, 3, 5, 7, and 10 years following SRS were 80%, 55%, 48%, 38%, and 23%, respectively. Multivariate analysis revealed that pretreatment ipsilateral pure tone average (p < 0.001) and tumor size (p = 0.009) were statistically significantly associated with time to nonserviceable hearing. Conclusions Durable hearing preservation a decade after low-dose SRS for VS occurs in less than one-fourth of patients. Variables including preoperative hearing capacity and tumor size may be used to predict hearing outcomes following treatment. These findings may assist in pretreatment risk disclosure. Furthermore, these data demonstrate the importance of long-term follow-up when reporting audiometric outcomes following SRS for VS.

AbstractBackgroundTOMM40 (translocase of the outer mitochondrial membrane pore subunit) is in linkage disequilibrium with apolipoprotein E (APOE). APOE e4 is linked to long (L; 21–29 T residues) poly‐T variants within intron 6 of TOMM40, whereas APOE e3 can be associated with either a short (S; <21 T residues) or very long (VL; >29 T residues) variant. To assess the possible contribution of TOMM40 to Alzheimer's disease onset, we compared the effects of TOMM40 and APOE genotype on preclinical longitudinal memory decline.MethodsAn APOE e4–enriched cohort of 639 cognitively normal individuals aged 21 to 97 years with known TOMM40 genotype underwent longitudinal neuropsychological testing every 2 years. We estimated the longitudinal effect of age on memory using statistical models that simultaneously modeled cross‐sectional and longitudinal effects of age on the Auditory Verbal Learning Test Long‐Term Memory score by APOE, TOMM40, and the interaction between the two.ResultsThere were significant effects overall for both TOMM40 (linear effect, P = .04; quadratic effect, P = .03) and APOE (linear effect, P = .06; quadratic effect, P = .008), with no significant interaction (P = .63). In a piecewise model, there was a significant TOMM40 effect before age 60 years (P = .009), characterized by flattened test–retest improvement (VL/VL subgroup only) but no significant APOE effect, and a significant APOE effect after age 60 years (P = .006), characterized by accelerated memory decline (e4 carriers) but no significant TOMM40 effect.ConclusionBoth TOMM40 and APOE significantly influence age‐related memory performance, but they appear to do so independently of each other.